Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1

Yang, Xue; Zhang, Manling; Xie, Bingxian; Peng, Zishan; Manning, Janet R.; Zimmerman, Raymond J.; Wang, Qin; Wei, An-Chi; Khalifa, Moustafa; Reynolds, Michael; Jin, Jennifer; Om, Matthew; Zhu, Guangshuo; Bedja, Djahida; Jiang, Hong; Jurczak, Michael J.; Shiva, Sruti; Scott, Iain; O’Rourke, Brian; Kass, David A.; Paolocci, Nazareno; Feng, Ning

doi:10.1093/cvr/cvac096

Cited by 21 publications

(20 citation statements)

References 52 publications

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“…32 Moreover, we recently showed that BDNF regulates cardiac bioenergetics by modulating the expression of the transcription factor Yin Yang1. 33 With overt HF, as in the case of chronic LV dysfunction occurring 4 weeks after infarcted in mice, 20 the initial compensatory sympathetic overdrive 34,35 becomes maladaptive, altering βARs sensitivity/coupling to G proteins, ultimately lowering cardiac contractility/inotropic reserve. 35 Among other signatures of adrenergic dysregulation, there is a substantial loss of β1AR density (≅50%) at the plasma membrane level and a marked dysfunction of β3AR, too.…”

Section: Bdnf and βAr Signaling In Chfmentioning

confidence: 99%

β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure

Cannavò

Jun

Rengo

et al. 2023

Circulation Research

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Background: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, β-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the β-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. Methods: We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in WT, β3AR KO, or myocyte-selective BDNF KO (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). Results: In WT hearts, BDNF levels rose early after MI (<24 hours), plummeting at 4 weeks when LV dysfunction, adrenergic denervation, and impaired angiogenesis ensued. The TrkB agonist, LM22A-4, countered all these adverse effects. Compared with WT, isolated myoBDNF KO hearts displayed worse infarct size/LV dysfunction after I/R injury and modest benefits from LM22A-4. In vitro, LM22A-4 promoted neurite outgrowth and neovascularization, boosting myocyte function, effects reproduced by 7,8-dihydroxyflavone, a chemically unrelated TrkB agonist. Superfusing myocytes with the β3AR-agonist, BRL-37344, increased myocyte BDNF content, while β3AR signaling underscored BDNF generation/protection in post-MI hearts. Accordingly, the β1AR blocker, metoprolol, via upregulated β3ARs, improved chronic post-MI LV dysfunction, enriching the myocardium with BDNF. Last, BRL-37344-imparted benefits were nearly abolished in isolated I/R injured myoBDNF KO hearts. Conclusions: BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac β3AR stimulation, or β-blockers (via upregulated β3AR), is another BDNF-based means to fend off chronic postischemic heart failure.

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Section: Bdnf and βAr Signaling In Chfmentioning

confidence: 99%

β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure

Cannavò

Jun

Rengo

et al. 2023

Circulation Research

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“…TAC procedure was performed as previously described (Yang et al, 2022). Briefly, sterile surgery was performed in our dedicated facility.…”

Section: Star✶methodsmentioning

confidence: 99%

“…The chest was then closed with a 6-0 proline suture and 5-0 silk suture. Serial echocardiography was performed in sedated mice (TAC) and conscious mice (12-months-old) as described previously (Yang et al, 2022).…”

Section: Star✶methodsmentioning

confidence: 99%

Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart

Zhang

Feng

Thapa

et al. 2022

Preprint

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General Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodynamic stress is largely unknown. Here, we show that cardiomyocyte-specific GCN5L1 knockout mice (cGCN5L1 KO) display exacerbated pressure overload-induced heart failure progression following transaortic constriction (TAC). Mitochondrial DNA and mitochondrial electron transport chain protein levels were decreased in cGCN5L1 KO hearts after TAC, and isolated neonatal cardiomyocytes with reduced GCN5L1 expression had lower bioenergetic output in response to hypertrophic stress. Loss of GCN5L1 expression led to a decrease in the acetylation status of mitochondrial transcription factor A (TFAM) after TAC in vivo, which was linked to a reduction in mtDNA levels in vitro. Together, these data suggest that GCN5L1 may protect from hemodynamic stress by maintaining mitochondrial bioenergetic output.

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“…As previously described, 44 hearts from 1–2-day old Sprague Dawley rat pups were excised into cold buffer (NaCl 137mM, KC1 5.36mM, MgSO4– 7H2O 0.81mM, dextrose 5.55mM, KH2PO4 0.44mM, Na2HPO4–7H2O 0.34mM, and HEPES 20mM at pH 7.5). Ventricles were cleared of blood and dissected into 1–2mm pieces to digest out cardiomyocytes using multiple incubations in trypsin (0.04%) and collagenase (0.4mg/ml) at 37°C on a rocking platform.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were cultured in serum free DMEM containing 0.1% Insulin-transferrin-selenium (Thermo Fisher Scientific). 44…”

Section: Methodsmentioning

confidence: 99%

Myoglobin promotes cardiomyocyte differentiation through oxidatively modulating the Hippo Kinase Pathway

Rao

Rochon

Singh

et al. 2022

Preprint

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Background: While cardiomyocytes undergo terminal differentiation postnatally and rarely re-enter the cell cycle, the endogenous mechanisms that propagate differentiation and prevent de-differentiation remain unclear. The monomeric heme protein myoglobin, which stores oxygen and regulates reactive oxygen/nitrogen species balance in the heart, increases in expression by over 50% during cardiomyocyte differentiation. Though myoglobin deletion without significant compensation is embryonic lethal in mice, a role for the protein in regulating cardiomyocyte differentiation has not been tested. We hypothesized that myoglobin expression is required for cardiomyocyte differentiation and the loss of myoglobin enables de-differentiation. Methods: Myoglobin was genetically silenced in HL-1, H9C2 cells, and neonatal rat ventricular cardiomyocytes (NRVM) to examine myoglobin-dependent effects on differentiation, proliferation, and Hippo pathway signaling. A zebrafish model of Mb depletion was made using CRISPR-Cas9 to test the effect of myoglobin depletion on cardiac regeneration after apical resection injury in vivo. Results: Myoglobin deletion in cultured cell lines and NRVM decreased the gene expression of cardiomyocyte differentiation markers (troponin, myosin light chain, and myosin heavy chain), upregulated markers of dedifferentiation (runx1 and dab2) and stimulated cell proliferation. Mechanistically, we show that the heme prosthetic group of myoglobin catalyzes the oxidation of the Hippo pathway kinase LATS1, which activates the enzyme to phosphorylate the downstream Yes associated protein (YAP) transcription factor, which prevents its transcriptional activity. Thus, the loss of myoglobin results in the de-phosphorylation and nuclear translocation of YAP, which propagates proliferation and fetal gene expression. In vivo, myoglobin-deficient zebrafish hearts recapitulated the increase in YAP signaling and showed accelerated regeneration at 20 days post apical injury.

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Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1

Cited by 21 publications

References 52 publications

β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure

β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure

Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart

Myoglobin promotes cardiomyocyte differentiation through oxidatively modulating the Hippo Kinase Pathway

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